START Stewardship Tactics for Antimicrobial Resistance Trends

empiric antimicrobial therapy. 4. Weigh cost-containment strategies for appropriate antimicrobial therapies. 5. Discuss the goals of antimicrobial stewardship and roles of key team members in running a stewardship initiative.


Today's Health Care Environment
Among infectious diseases, community-acquired pneumonia (CAP) is the leading cause of death in the United States and is associated with billions of dollars in health care costs. 1,2 Despite the availability of several classes of antimicrobial agents, elevated resistance rates challenge appropriate antimicrobial selection and increase the risk of treatment failure. Against this backdrop, antimicrobial stewardship programs (ASPs) are being implemented in a growing number of institutions with the goal of encouraging the appropriate use of antimicrobial agents to optimize clinical outcomes while minimizing unintended consequences, including the emergence of resistance.
Appropriate management of hospitalized patients with CAP through effective ASPs has several potential benefits-reduction in morbidity, mortality, and overall health care costs associated with CAP. However, studies are needed to fully evaluate the benefits of ASPs in CAP management. An effective and successful ASP is dependent on the multidisciplinary team responsible for treating the hospitalized patient with CAP-the infectious diseases (ID) specialist, the clinical pharmacist, and other members-serving as a passionate advocate for appropriate antimicrobial use. Educating personnel on the issues related to antimicrobial use and resistance when managing patients with CAP is essential. As a result, several ID physicians and pharmacists from across the country are becoming involved in the START educational program to address this critical need at both the regional and local levels.

What Is START ?
The START (Stewardship Tactics for Antimicrobial Resistance Trends) educational program commenced in 2006 and has been repeated in each subsequent year as a series of regional meetings originally designed for hospital-based pharmacists. The program was subsequently expanded to include physicians and other health care personnel interested in learning about the latest guidelines and management strategies related to CAP and antimicrobial stewardship.
The objective of the START educational program was to educate and familiarize the health care team on the following topics: • The epidemiology and impact of hospital-acquired infections in U.S. hospitals • The common pathogens associated with CAP and national and regional resistance trends • The importance of pharmacokinetics and pharmacodynamics as factors in appropriate selection of empiric antimicrobial therapy • Cost-containment strategies for appropriate antimicrobial therapies • The goals of antimicrobial stewardship and roles of key team members in running a stewardship initiative This supplement reflects the topics covered in the START program. Three articles are based on the 3 main talks from the START program while a fourth article answers the most commonly asked questions during START meetings.

Overview
In the first article, Dr. Thomas M. File, Jr., discusses new guidelines for the diagnosis and treatment of CAP released in 2007 by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS). 3,4 These guidelines, intended as an update of the 2003 IDSA guidelines, provide evidence-based recommendations for proper management of patients with CAP and address several issues that are evolving in the management of these patients. A portion of the guidelines is devoted to choosing the appropriate site of care guided by mortality prediction tools. This is to ensure that hospitalization is reserved only for those who require it-a response to manage the rising cost of health care. The guidelines also address increasing resistance, selection of the most appropriate therapy, monotherapy versus combination therapy, and the optimal duration of therapy.
The second article, by Dr. David P. Nicolau, addresses cost considerations when treating patients with CAP. The article emphasizes that clinical outcome is only one aspect of gauging the success of patient management strategies. Given the growing economic burden, the health care team must also take into account tactics that improve cost-effectiveness. When considering hospitalization costs, length of stay is a major portion of overall health care cost, while antimicrobial agents are a relatively small proportion of overall cost. 5,6 Not surprisingly, antimicrobial resistance and subsequent treatment failure is a major reason for high costs. The article discusses several tactics that can be used to improve cost-effectiveness while maintaining the quality of care, including choosing the appropriate agent, optimizing dosing (improving the probability of a successful clinical outcome while minimizing the risk of resistance development), active IV-to-oral switch therapy, and short-course regimens.
Dr. Richard H. Drew, in the third article, discusses the role of ASPs in management of infection and presents strategies that can be used to improve the appropriate use of antimicrobials. Excessive and inappropriate use of antimicrobials may render commonly used agents ineffective and lead to an increase in unintended consequences, including the emergence and spread of resistant bacteria. As a result, the guidelines on antimicrobial stewardship were released in 2007 by IDSA and the Society for Healthcare Epidemiology of America (SHEA). 7 These guidelines provide important insights on implementing an ASP at an institution and present evidence pertaining to core strategies that can provide both clinical and economic benefits. The success of stewardship programs is based on the collaborative effort of physicians, pharmacists, infection control personnel, and other health care professionals with the support of hospital administrators. The fourth article in this supplement discusses a number of questions from the participants that were addressed during the START meetings. This article offers an opportunity to discuss various topics that were not normally covered within the presentations but are relevant to the everyday practice of hospital clinicians. Author C ommunity-acquired pneumonia (CAP) along with influenza is the leading cause of death among infectious diseases in the United States (and eighth leading cause of death overall). 1 Five to 6 million cases occur each year, with persons 65 years or older accounting for about one million cases. 2 An estimated 20% of the patients with CAP require admission to the hospital. 3 The mortality rate of patients who require admission to the hospital averages 12% overall but increases to 30%-40% for those with severe CAP who require admission to the ICU. 2 This compares to a mortality rate of less than 1% among patients with CAP treated on an outpatient basis. 4 In addition to the clinical consequence of CAP, the economic cost is extraordinary, with one study estimating the cost for each inpatient episode of CAP to exceed $10,000. 3 It is noteworthy that these clinical and economic consequences of CAP occur against the backdrop of effective antimicrobial agents available for the treatment of respiratory tract infections. Many factors must be considered in order to select an appropriate antimicrobial regimen for effectively treating patients with CAP. The first and foremost consideration should be whether an antimicrobial agent is warranted. Viral infections can play a role in a significant portion of patients hospitalized for CAP, with estimates ranging from 1% to 23%. 5 Several observational studies have shown that over 50% of the patients with viral respiratory tract infections are inappropriately prescribed antimicrobial agents. 6,7 Antimicrobial overuse and inappropriate antimicrobial selection have been associated with increased drug resistance among several respiratory pathogens. In addition, unnecessary use increases cost and potential adverse events.
Increasing resistance has made judicious use of antimicrobials an imperative, 8 and differentiating viral bronchitis from pneumonia is key in limiting unnecessary antimicrobial use. Unfortunately, there is lack of rapidly available, cost-effective diagnostic tests that reliably differentiate self-limiting viral infections from bacterial infections. However, practice guidelines can offer pragmatic criteria for better antimicrobial usage. 9 Once a patient is diagnosed with CAP, optimal management should be based on the site of care, the severity of CAP, the resistance profiles of bacteria, and the pharmacokinetic-pharmacodynamic targets that ensure bacterial eradication.

Site of Care
Site of care in patients with CAP impacts the overall cost of treatment, the intensity of diagnostic testing, and options for empiric antimicrobial selection. The decision to admit a patient with CAP is based on (a) mortality prediction rules, such as the PORT (Pneumonia Outcomes Research Team) Severity Index (PSI) score or CURB-65 (Confusion, Urea concentration, Respiratory rate, Blood pressure, and age > 65), (b) social circumstances of the patient, and (c) co-existing conditions.
Hospitalization. Hospitalization should be considered when (a) patients have pre-existing conditions that may compromise the safety of home care, (b) patients have hypoxemia, (c) patients are unable to take oral medications, or (d) psychosocial factors can potentially impact effective treatment (such as an unstable home environment or psychiatric disorders that may hinder adherence to therapy). 9 Mortality prediction tools can also help guide clinicians in making the decision to hospitalize the patient.
The PORT Prediction Rule, developed over 10 years ago, offers important insights into the risk of mortality ( Figure 1). 10 This technique uses a combination of demographic variables, co-morbidities, physical observations, and laboratory and radiographic variables to assign patients to 1 of 5 classes. Those belonging to PSI Class 1 or 2 have a low risk of mortality (< 1%) and can be treated as outpatients. Those in PSI Class 3 have a slightly higher risk of mortality (< 5%) and may require a brief observational stay in a hospital. Those in PSI Class 4 or 5 have the highest mortality risk (8%-30%) and will require hospitalization-those in PSI Class 5 should be admitted to an ICU. Though the PORT Prediction Rule is effective in determining mortality risk, it is not the most practical approach in the clinical setting as it is based on laboratory findings that can be costly and time consuming.
The CURB-65 Rule uses 5 aspects in making a clinical determination-confusion, urea concentration, respiratory rate, blood pressure, and age ( Figure 2). 11 Those meeting 2 or more of the criteria should be considered for hospitalization. However, this method requires a blood sample and laboratory analysis for urea concentration. In response to this, the CRB-65 was designed. It omitted the blood urea measurement and was practical for officebased settings. 12 In CRB-65, a score of 0 equates to home treatment, a score of 1 to hospital-supervised treatment, and a score of 2 or more to hospitalization.
A study comparing the mortality rates using PSI, CURB-65, and CRB-65 showed a strong correlation among the 3 methods. 12 Admission to the ICU. Recommendation regarding admission to the ICU is provided by the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines about management of CAP. According to the IDSA/ATS guidelines, direct admission to the ICU is essential for patients with septic shock requiring vasopressor or for patients with acute respiratory failure requiring intubation and mechanical ventila-tion. 9 ICU admission should also be considered for patients who have 3 or more of the following: confusion/disorientation, uremia (blood urea nitrogen ≥ 20 mg per dL), respiratory rate ≥ 30 breaths/minute, hypotension requiring aggressive fluid resuscitation, PaO2/FiO2 ratio ≤ 250, multilobar infiltrates, leukopenia (WBC < 4000 cells/mm 3 ), thrombocytopenia (platelet count < 100,000 cells/mm 3 ), or hypothermia (core temperature < 36°C).

Bacterial Etiology of CAP
Bacterial etiology varies slightly according to the severity of CAP (Table 1). 5 Streptococcus pneumoniae remains the most common cause of CAP across all severities. Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae are associated with mild-to-moderate CAP and Staphylococcus aureus, Legionella species, and gram-negative pathogens, including Klebsiella pneumoniae and Pseudomonas aeruginosa, are more likely to be associated with severe CAP. Recently, communityassociated methicillin-resistant Staphylococcus aureus (MRSA) has also been observed as a cause of severe CAP. The probable causative pathogens influence the diagnostic measures and empiric treatment strategies, including the use of combination therapy and gram-negative coverage.

Bacterial Resistance
Among community-acquired respiratory tract pathogens, S. pneumoniae remains the primary focus given its predominance as the causative pathogen, including severe infections 5 and antimicrobial resistance to several commonly used agents. [13][14][15][16][17] Multiple antimicrobial surveillance programs have been instituted in the United States to track the susceptibility trends of S. pneumoniae.
Penicillin Resistance. Increasing penicillin resistance of S. pneumoniae has been reported since the early 1990s with a peak at about 40% (high-level plus intermediate-level resistance) in 2000 ( Figure 3). [13][14][15] Since 2000, resistance to penicillin has remained stable, though at an elevated level. A surveillance study in 2005-2006 involving 1,543 isolates showed high-level penicillin resistance at 16% and intermediate resistance at 21%. 16 The clinical relevance of penicillin-resistant S. pneumoniae (PRSP) is controversial. Available data suggest that clinically relevant levels of penicillin resistance most likely occur at a minimal inhibitory concentration (MIC) of ≥ 4 μg per mL. This is reflected in the new 2008 Clinical and Laboratory Standards Institute breakpoints (formerly NCCLS) for parenteral penicillin G-susceptible (≤ 2 μg per mL), intermediate (4 μg per mL), and resistant (≥ 8 μg per mL)-for nonmeningeal infections such as CAP. 18 These changes will reduce the reported rate of resistance and hopefully assist clinicians in predicting which patients are at a greater risk for clinical failure due to a resistant strain.
Macrolide Resistance. Macrolide resistance of S. pneumoniae has increased steadily since the 1990s, approaching 30% by the early 2000s ( Figure 3). 15, 17 The level of macrolide resistance has remained steady over the past few years, though a recent surveillance study from 2005-2006 estimated 34% macrolide resistance in the United States. 16 Fluoroquinolone Resistance. Fluoroquinolone resistance of S. pneumoniae is rare-surveillance studies demonstrate resistance rates of 1% or less. 13  and 0.2% intermediate resistance). 16 Despite the continued low level of resistance to fluoroquinolones, it is important to use them judiciously to preserve their utility. Antimicrobial Resistance by Geographic Region. Antimicrobial resistance can vary considerably by geographic region. The Prospective Resistant Organism Tracking for the Ketolide Telithromycin (PROTEKT) study showed that the highest levels of penicillin and macrolide resistance were in the southeastern and south-central regions of the United States (high-level penicillin resistance of 33%-36% and macrolide resistance of 39%-40%), and the lowest were in the northwestern region (high-level penicillin resistance of 17% and macrolide resistance of 23%). 13 Therefore, the knowledge of local resistance profiles is critical to guide appropriate selection of an antimicrobial agent.
Clinical Impact of Resistance. The clinical relevance of β-lactam resistant pneumococcal pneumonia appears most relevant to specific MICs for specific antimicrobials. 19 Many studies are hampered by small sample sizes, biases inherent in observational design, and the relative infrequency of clinical isolates showing high-level resistance. One study evaluated time to symptom resolution in 17 pneumococcal pneumonia patients (5 of whom were infected with a penicillin-resistant strain) who were treated with procaine penicillin. 20 Those with a resistant infection experienced a longer time before resolution of fever (3.6 vs. 1.9 days), cough and sputum production (6.0 vs. 2.7 days), and pleuritic pain (3.6 vs. 2.1 days), compared to patients with susceptible infections. In a study from the Centers for Disease Control and Prevention of bacteremic pneumococcal pneumonia, investigators found that after hospital day 4, the risk of death was 7 times greater in patients infected with high-level PRSP (MIC ≥ 4.0 µg per mL; 19/1,151 patients) than in patients infected with intermediate isolates (MIC = 0.012-1.0 µg per mL; 81/1,151 patients). 21 However, treatment and severity of disease were not recorded.
Subsequently, a follow-up, case-control study of patients with bacteremic pneumococcal pneumonia was conducted, which addressed the limitations of the trial by Feikin et al. (2000) and controlled for risk factors, severity, and treatment. 22 The findings from this multivariate analysis showed no contribution of antimicrobial resistance to mortality or requirement for ICU admission, but determined that more important predictors of outcome included severity of illness and whether there was a "do not resuscitate" order on the patient's chart. Findings from a more recent large observational study suggest that current levels of β-lactam resistance generally do not cause treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone, cefotaxime) and doses are used. 23 However, discordant therapy with cefuroxime in patients with pneumococcal bacteremia has been associated with an excessively high failure rate com- Penicillin-Resistant and Macrolide-Resistant S. pneumoniae In Vitro a a Sources: Karchmer AW; 13 Doern GV, Brown SD; 14 The Alexander Network; 15 Karlowsky  pared with other discordant therapies The clinical impact of macrolide resistance is well established. Antimicrobial resistance is associated with an increased risk of breakthrough bacteremia in patients with CAP. In a prospective, population-based study by Daneman et al. (2006), pneumococcal bacteremia cases were identified among patients who received macrolide treatment. 24 These treatment failures were then documented based on the isolate MIC. Clinical failure was observed in 1.5% (21 of 1,397) of episodes where isolates were susceptible to erythromycin (MIC ≤ 0.5 μg per mL) but it was 16% (37 of 230) for infections caused by resistant strains (MIC ≥ 1 μg per mL). Other studies are associated with similar results suggesting that macrolide resistance can be an important cause of clinical failure. [25][26][27] Several case reports of treatment failures due to fluoroquinolone-resistant pneumococcal infections in adults with CAP have also been reported. 28,29 Many of the patients described in these reports had been previously treated with fluoroquinolones.
Risk Factors for an Antimicrobial-Resistant Infection. Given the clinical significance of antimicrobial resistance, it is important to identify factors that may increase the risk of an infection by a resistant organism. These include age (either > 65 years or < 5 years), noninvasive disease, alcoholism, exposure to a child who attends day care, or multiple co-morbidities. [30][31][32] Prior exposure to an antimicrobial is also a major cause of antimicrobial resistance. 30,31 One study showed that exposure to a β-lactam in the previous 3 months significantly increased the risk of peni-cillin resistance in a subsequent infection. 30 Prior macrolide use has also been shown to increase the risk of a macrolide-resistant infection, though the risk is significantly greater with prior azithromycin use than with prior clarithromycin or erythromycin use. 31 Prior fluoroquinolone use also increases the risk of a fluoroquinolone-resistant infection. 31 The strong association of prior antimicrobial use with subsequent antimicrobial resistance should be an important consideration when selecting empiric therapy for patients with CAP. Antimicrobial usage during the previous 3 months should be noted for each patient, and if possible, a different antimicrobial class should be used.

Selecting the Appropriate Antimicrobial Regimen
Goal of Therapy. Inappropriate treatment can lead to failed bacterial eradication, the selection of resistant bacteria, complications due to the spread of these organisms, and a resulting infection that is more challenging to treat. The goal of appropriate antimicrobial treatment, therefore, is to maximally reduce or eradicate the bacterial load in order to achieve clinical success and minimize the potential for development of resistance. To minimize the risk of resistance development, current IDSA/ ATS guidelines suggest reducing the duration of therapy to a minimum of 5 days, though a longer duration may be required if the initial therapy was not active against the infection or if an extrapulmonary infection exists. 9 a Source: Mandell LA, et al. 9 b If community-associated methicillin-resistant Staphlococcus aureus (MRSA) is a concern, add vancomycin or linezolid. CAP = community-acquired pneumonia; IDSA/ATS = Infectious Diseases Society of America/American Thoracic Society.  33 Therefore, increased dosing of these agents by increasing the Cmax and AUC would maximize their ability to eradicate bacteria. Optimizing pharmacokinetic-pharmacodynamic parameters is the rationale for the development of the 750 mg, 5-day levofloxacin regimen in contrast to the traditional 500 mg, 10-day course. Increasing the levofloxacin dose from 500 mg to 750 mg nearly doubles the AUC and increases the AUC/MIC ratio, thus increasing the probability of achieving pharmacokinetic-pharmacodynamic targets. 34 A randomized, double-blind, clinical trial showed no significant differences between the 2 regimens even when stratified by disease severity. 35 Moreover, the short-course regimen is associated with less total drug usage, which can potentially reduce the risk of emergence of resistance.
A prospective, randomized, double-blind trial compared moxifloxacin (400 mg daily) and levofloxacin (500 mg daily) for 7-14 days for the treatment of hospitalized, elderly patients (≥ 65 years) with CAP. 41 At the test-of-cure visit, there was no significant difference in the clinical cure rate between the moxifloxacin group (92.9%) and the levofloxacin group (87.9%, P = 0.2), even when patients were stratified by disease severity or age. However, at the on-treatment visit (3 to 5 days after the start of therapy), a significantly greater percentage of patients receiving moxifloxacin had achieved clinical recovery than those receiving levofloxacin (97.9% vs. 90.0%, P = 0.01). This study suggests that using a more potent agent may allow for more rapid resolution of CAP symptoms. It is important to note that this trial used a levofloxacin dose of 500 mg and not the 750 mg dose currently recommended by IDSA/ATS Guidelines. 9

Summary
When managing patients with CAP, it is important to choose the most appropriate site of care as it impacts the extent of diagnostic testing, the empiric selection of antimicrobials, as well as the overall health care costs. Hospital and ICU admission should be reserved for the more severely ill patients who are at a greater risk of death. For all disease severities, S. pneumoniae is the most common cause. Resistance of this pathogen is prevalent and growing and local resistance profiles should be consulted before selecting empiric therapy. Rapid initiation of appropriate antimicrobial therapy is critical in achieving successful clinical outcomes. Newer dosing regimens are attempting to optimize the pharmacokineticpharmacodynamic parameters of agents to ensure successful and more rapid eradication of the bacterial pathogen.

IDSA/ATS Guidelines for Empiric Treatment of CAP.
The IDSA/ATS guidelines for the empiric treatment of patients with CAP take into account the site of care and the potential pathogens ( Figure 4). 9 For hospitalized patients in the general medical ward, monotherapy with a respiratory fluoroquinolone (levofloxacin, moxifloxacin, or gemifloxacin) or combination therapy with a β-lactam and macrolide is generally recommended.
For severe cases requiring ICU admission, antimicrobial selection will depend on the presence of risk factors for Pseudomonas infection. P. aeruginosa, a typical hospital-acquired pathogen, is sometimes associated with CAP. The risk factors for infection by P. aeruginosa include a Gram stain consistent with a gram-negative infection, the presence of structural lung disease (bronchiectasis), repeated exacerbations of severe chronic obstructive pulmonary disease, corticosteroid therapy, recent broad-spectrum antimicrobial use, and malnutrition. 9 For patients with no risk of a Pseudomonas infection, combination therapy with a β-lactam and either a macrolide or a respiratory fluoroquinolone is recommended. For patients allergic to β-lactams, a respiratory fluoroquinolone and aztreonam are recommended. If methicillin-resistant S. aureus (MRSA) is suspected (such as the case if prior influenza-like illness, necrotizing severe pneumonia, or if a sputum Gram stain shows gram-positive cocci in clusters), vancomycin or linezolid should be added to the regimen.
Patients at risk of a Pseudomonas infection should be given combination therapy that includes an antipneumococcal/antipseudomonal β-lactam (e.g., piperacillin/tazobactam, cefepime, imipenem, meropenem) plus an antipseudomonal fluoroquinolone, or the above β-lactam plus an aminoglycoside and azithromycin or the above β-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for patients allergic to penicillin substitute aztreonam for the β-lactam). 9 Optimizing Pharmacokinetic and Pharmacodymanic Parameters. In addition to choosing an appropriate antimicrobial agent, it is important to use a regimen that optimizes a drug's pharmacokinetic-pharmacodynamic parameters to ensure bacterial eradication. For concentration-dependent agents, such as the fluoroquinolones, clinical outcomes and prevention of resistance

The Science of Selecting Antimicrobials for Community-Acquired Pneumonia (CAP)
Marco P. Cicero, PhD, of Vemco MedEd, LLC, contributed medical writing and editorial assistance. This article is being published as part of a supplement to the START continuing education program for pharmacists and physicians. It is supported by an educational grant from Schering-Plough Corporation.
David P. Nicolau, PharmD, FccP, FIDSa abStRact BACKGROUND: The overall health care costs for managing patients with community-acquired pneumonia (CAP) in U.S. hospitals is burdensome. While pharmacy costs comprise only a minor proportion of these costs, hospital length of stay (LOS) is the greatest contributor. Infections due to antimicrobial-resistant pathogens are also associated with increased overall health care cost. Therefore, strategies that aim to minimize antimicrobial resistance and reduce hospital LOS may have the greatest impact in reducing overall health care costs in managing patients with CAP.
OBJECTIVE: To evaluate how antimicrobial resistance can impact health care costs associated with CAP and review strategies to minimize the risk of resistance development while promoting appropriate antimicrobial therapy (including optimized dosing) and decreasing hospital LOS.
SUMMARY: Antimicrobial resistance can increase the risk of clinical failure and result in higher overall health care costs. Further development of antimicrobial resistance during therapy should, therefore, be minimized. This can be achieved through optimized antimicrobial dosing strategiesusing a higher dose of concentration-dependent agents or prolonged infusion of time-dependent agents-that increase the probability of attaining pharmacokinetic-pharmacodynamic targets for eradication of the pathogen and hence successful clinical outcomes. Decreasing LOS must be a priority when attempting to reduce hospital costs. Active intravenous-to-oral switch therapy has been shown to effectively reduce LOS. Appropriate short-course regimens may also offer the opportunity for effective treatment while reducing or eliminating unnecessary antimicrobial exposure that not only reduces the potential for drug-related adverse events, but may also minimize the selection of resistant organisms.
CONCLUSION: Clinical failure and antimicrobial resistance can significantly increase the cost of managing patients with CAP, primarily by increasing LOS. Therefore, strategies should be employed to minimize the risk of resistance development and reduce LOS. These include early appropriate therapy, optimized dosing based on pharmacodynamic principles, and efficient IV-to-PO switch therapy when appropriate.  [1][2][3] Given the rising costs of managing hospitalized patients, selection of appropriate antimicrobial therapy for CAP must take into account clinical effectiveness as well as cost-efficiency. Antimicrobial costs are under constant scrutiny. However, it is important to recognize that drug-acquisition costs as a percentage of overall cost of managing patients with CAP are small. The identification of other factors that can be targeted to reduce costs is necessary.

Antimicrobial Costs as a Proportion of Total Health Care Cost
Cost of drugs, and in particular antimicrobials, is often identified as the main reason for rising costs of health care in hospitalized patients. However, studies have shown that the proportion of overall management costs attributed to these agents is less than 5% for hospitalized CAP patients. 4,5 Studies that evaluated other serious infections in the hospital attribute less than 10% of overall health care costs to antimicrobials. [6][7][8][9] A recent study analyzed costs associated with managing hospitalized patients with CAP (PSI [Pneumonia Severity Index] Class IV and V) at a community health system during a 6-month period. 10 The median total hospital cost per patient was $5,078, while the antimicrobial acquisition cost accounted for $139 per patient (2.7% of the total cost). The biggest contributors to overall cost in this study were respiratory therapy (26%), room and board (22%), pharmacy costs (17%), and laboratory costs (14%). This study indicates that efforts focusing on shortening hospital length of stay (LOS) may be more effective in reducing hospital expenditures than those aimed at reducing antimicrobial drugacquisition costs.
Moreover, drug-acquisition cost is only one aspect of overall cost of therapy. Other drug-related costs include resources associated with drug administration and preparation, diagnostic testing (such as monitoring drug concentration levels), and drug-related adverse events or allergic reactions.

Impact of Antimicrobial Resistance on Cost
Patients with infections caused by antimicrobial-resistant organisms are at a greater risk of delayed or inappropriate therapy. This increases the probability of clinical failure, and these infections are typically associated with higher morbidity and mortality. In addition to clinical failure, antimicrobial resistance has been shown to increase overall health care costs (Table 1). 11 Macrolide Resistance Associated With Clinical Failure. Macrolide resistance has been associated with clinical failure in several studies. 12,13 A prospective, population-based study conducted in Canada from 2000 to 2004 assessed if macrolide resistance resulted in increased failure rates in pneumococcal bacteremia cases. 14 Macrolide failure was defined as bacteremia that occurred during treatment with outpatient macrolide antimicrobials or within 2 days after completing the course of macrolide therapy. Although macrolide failure occurred in 3.5% of the nearly 1,700 episodes included in the study, failures were cess rates were not significantly different when comparing areas with higher versus lower endemic macrolide resistance rates; however, there were significant differences in cost. Table 2 shows the treatment cost by clinical outcome and by initial treatment (macrolide or a fluoroquinolone). In each case, cost of treatment was significantly higher in areas where endemic macrolide resistance was higher.
Penicillin Resistance Associated with Higher Health Care Costs. Penicillin resistance can also result in higher health care costs. Klepser et al. conducted a single-center, retrospective, observational cohort study of 231 hospitalized patients infected with S. pneumoniae isolated from blood or respiratory tract samples from 1995 to 1998. 17 Data were collected for 36 days following the first positive culture and grouped according to penicillin susceptibility. No differences were observed when comparing the clinical outcomes between patient groups. However, patients infected with a nonsusceptible isolate (n = 142) had a longer median stay (14 days vs. 10 days; P < 0.05) and a higher total median cost ($1,600 difference, 95% CI = $257-$2,943) when compared with patients infected with a susceptible strain (n = 89).

Antimicrobial-Resistant Gram-Negative Bacteria Associated With Higher Health Care Costs.
Antimicrobial-resistant gramnegative bacteria, such as extended-spectrum β-lactamase-(ESBL-) producing Klebsiella pneumoniae or Escherichia coli have also been shown to result in higher overall costs. 18 This is likely the result of an increased probability of delayed appropriate therapy, resulting in higher mortality rates and prolonged hospital LOS.
Resistance May Impact Clinician Prescribing Behavior. Antimicrobial resistance can also have a global impact on treatment decisions. Clinician perception of resistance can affect prescribing behaviors when selecting empiric therapy. 19 Therefore, not unexpectedly, in this situation of perceived "unacceptably high" resistance, more potent antimicrobial agents or combination regimens may be unnecessarily used for empiric treatment. This phenomenon then feeds the inappropriate or overuse of antimicrobials for a great many patients and highlights the need for the dissemination of local susceptibility data to the practicing prescribers of the region.

Containing Costs and Containing Bugs: Are They Mutually Exclusive?
significantly lower when the minimum inhibitory concentration (MIC) of the isolates was ≤ 0.25 μg per mL (1.5%) than when the MIC of the isolates was 1 μg per mL (38%; P < 0.001). Isolates with MIC > 1 μg per mL were not associated with further increases in failure, suggesting that even low-level macrolide resistance increases the risk of failure.
Macrolide Resistance Associated With Higher Health Care Costs. A multicenter, retrospective, observational study involved 122 patients with CAP due to S. pneumoniae who required hospitalization after failing to respond to initial outpatient treatment with a macrolide for 2 or more days. 15 Over half of the patients had bacteremia, and 71% were infected with a macrolide-resistant strain. Overall, the mean hospital LOS was 8.7 days, including 1.3 days in a critical care unit and 1.4 days of mechanical ventilation. The mean cost of treating a patient with a macrolideresistant infection was $5,139 higher than the cost of treating a patient infected with a macrolide-susceptible strain ($14,153 vs. $9,014; P = 0.011). Among patients with bacteremia, the cost of treating those infected with a resistant strain was nearly double compared to the cost of treating those infected with a susceptible strain ($16,563 vs. $8,537, P = 0.004).
Macrolide resistance in the community can also impact overall health care costs of CAP. A retrospective analysis used a large clinical database to obtain treatment outcome and cost data associated with CAP patients in 23 metropolitan areas. 16 Surveillance data were used to identify macrolide resistance rates for each area, and outcomes and costs were compared based on macrolide resistance rates of < 25% or ≥ 25% for the area. The clinical suc-

Concentration-Dependent Agents.
For concentration-dependent agents, such as the aminoglycosides and fluoroquinolones, successful outcomes have been associated with meeting targets related to the peak concentration to the minimum inhibitory concentration (MIC) ratio (Cmax/MIC) or the area under the concentration-time curve to MIC ratio (AUC/MIC). 25 For these agents, maximizing exposure with higher doses or with less frequent dosing can be important strategies to optimize their pharmacodynamic parameters.
As a result of pharmacodynamic studies, the recommended dosing of aminoglycosides has changed from the traditional 2-3 times daily to once daily. This change in aminoglycoside dosing not only increases the Cmax/MIC but has also been shown to decrease the potential for toxicity. 26 For the fluoroquinolones, higher doses increase the probability of meeting AUC/MIC targets. For S. pneumoniae infections, an AUC/MIC ratio of 30-35 is generally needed for successful clinical outcomes. The 750 mg dose of levofloxacin nearly doubles the AUC compared to the 500 mg dose and increases the probability of meeting AUC/MIC targets, particularly for isolates with higher MIC values. 27,28 However, evidence also suggests that an AUC/MIC ratio of 100 is needed to prevent the development of resistance. For S. pneumoniae infections, while both levofloxacin and moxifloxacin reach the concentrations needed for clinical effectiveness, only moxifloxacin attains the levels required to prevent development of resistance. 29 For gram-negative infections treated with the fluoroquinolones, an AUC/MIC ratio of 100-125 is generally recommended. 22,23

Strategy to Reduce Antimicrobial Costs: IV-to-PO Switch
Early intravenous-to-oral (IV-to-PO) switch therapy is a proven strategy to reduce overall health care costs without impacting clinical outcomes in patients with CAP. Studies beginning in the mid-1990s had shown evidence that critical pathways that actively select patients for IV-to-PO switch can decrease antimicrobial acquisition costs and reduce hospital LOS. [30][31][32][33][34] Ramirez et al. investigated the impact of an early switch to oral antibiotics (within 3 days of hospitalization) in 133 patients with CAP. 31 Criteria for early switch included improving cough and shortness of breath, temperature below 37.8° C for at least 8 hours, normalizing white blood cell count, and adequate oral intake and gastrointestinal absorption. Using similar criteria for switch, Kuti et al. also demonstrated that a pharmacist could manage the transition from IV-to-PO therapy and that these interventions could be initiated swiftly and safely, thereby reducing the LOS and the overall cost of care. 35 Candidates for IV-to-PO Switch Therapy. The latest CAP guidelines issued by the Infectious Diseases Society of America and the American Thoracic Society (IDSA/ATS) support early IV-to-PO switch therapy and provide recommendations for selecting patients appropriate for an IV-to-PO switch. 36 According to these guidelines, IV-to-PO switch therapy should be considered in patients who are hemodynamically stable, improving clinically, able to ingest oral medications, and have a normally functioning gastrointestinal tract. The guidelines also suggest that patients should be discharged as soon as they are clinically A study that investigated the relationship between amoxicillin-resistance levels with the per-patient cost of treatment for community-acquired lower respiratory tract infections showed a clear trend of increased costs as the probability of resistance increased. 20 Therefore, strategies to minimize the risk of resistance development during treatment will be critical in extending the usefulness of current antimicrobial agents and reducing overall treatment costs.

Strategy to Minimize the Emergence of Resistance: Optimizing Antimicrobial Dosing
Dosing regimens are now designed to attain pharmacodynamic targets that increase the probability of achieving clinical efficacy and prevent the emergence of resistance. Antimicrobial agents can be classified into 2 groups-those that exhibit concentration-dependent bacterial killing and those that exhibit time-dependent bacterial killing. The characteristics of the drug dictate pharmacokinetic/pharmacodynamic targets that should be achieved (Table 3). 21,22 Time-Dependent Agents. For time-dependent agents such as the β-lactams (penicillins, cephalosporins, and carbapenems), the proportion of time the drug concentration remains above the MIC during a dosing interval (T > MIC) should be considered. The optimal T > MIC varies depending on the class of agents-it is 40% for the carbapenems and 60%-70% for the cephalosporins. 23 Strategies to increase the T > MIC include shortening the dosing interval (without a subsequent increase in the dose) and extending the infusion time of intravenous agents (through continuous or prolonged infusion, which decreases the peak concentration [Cmax] but prolongs the T > MIC without increasing the dose). 23 Using higher doses will not necessarily have a significant impact on T > MIC (that is, doubling the dose will not necessarily double the T > MIC). 24 If susceptibility results are available for the infecting organism, optimized dosing strategies may also involve using an agent with a lower MIC for that particular pathogen in order to increase the T > MIC. and only about half of the patients were converted to oral therapy (Table 5). Forty-six percent were treated completely with an IV regimen, while several different agents were used for switch therapy among those who received oral formulations.

Containing Costs and Containing Bugs: Are They Mutually Exclusive?
• During the period of pharmacist intervention recommending switch therapy to an oral agent, the strategy was to aggressively convert patients to oral levofloxacin. Since many patients were started on a β-lactam or a macrolide, physicians were reluctant to switch to a different class of agents, and some patients continued to receive a β-lactam or a macrolide for the duration of treatment, while only about 40% received oral levofloxacin. About 30% of the patients were not switched to an oral formulation. • During the period of pharmacist intervention recommending initiation of IV therapy with a fluoroquinolone followed by conversion to its oral formulation (sequential therapy), patients were started on an IV formulation of moxifloxacin and then switched to its oral formulation. During this period, 95% of the patients were converted to oral moxifloxacin, suggesting that sequential therapy may improve acceptance of IV-to-PO conversion by clinicians. In this study, IV antimicrobial costs were significantly lower during the period of sequential therapy ($108) compared with costs during no pharmacy intervention ($222) or switch therapy stable, have no other active medical problems, and have a safe environment for continued care. Inpatient observation while taking oral antimicrobials is not necessary. IV-to-PO switch should be typically done within 2-4 days of initiation of treatment, though this depends on the overall clinical condition of the patient. 37 It is important to note that certain patient or infection types are contraindicated for IV-to-PO switch therapy (Table 4). 38 Types of IV-to-PO Switch Therapy. IV-to-PO switch therapy is defined in several ways depending on the antimicrobial agents used. 37 Sequential therapy uses the same agent for both IV and oral formulations with similar potency. Switch therapy uses different agents for the IV and oral formulations while maintaining the same or similar potency.
Step-down therapy can use the same agent or different agents for the IV and oral formulations, though potency decreases with the oral formulation.
Some studies have investigated the differences in cost and clinical outcomes with each of these conversion strategies. A study by Dresser et al. compared sequential therapy with a fluoroquinolone (gatifloxacin) and step-down therapy with a cephalosporin ± a macrolide (IV ceftriaxone ± IV erythromycin, then oral clarithromycin). 5 There was no significant difference in clinical cure rates (98% with sequential therapy and 92% with step-down therapy) or in mean LOS (4.1 days for those receiving gatifloxacin and 4.9 days for those receiving ceftriaxone). However, the mean cost per patient was significantly lower with sequential therapy ($5,109) than with step-down therapy ($6,164, P = 0.011). The higher cost associated with step-down therapy was attributed to the nearly one-day increase in mean LOS driven by 4 clinical failures.
Sequential therapy has also been associated with improved efficiency of IV-to-PO conversion compared to switch therapy. Davis et al. compared antimicrobial use during 3 separate time periods: period of no pharmacist intervention (January-March 2001), period of pharmacist intervention to switch therapy to an oral agent (January-March 2002), and period of pharmacist intervention recommending initiation of IV therapy with a fluoroquinolone (moxifloxacin) followed by conversion to its oral formulation (sequential therapy) from January-March 2004. 38 • During the period of no pharmacist intervention, IV therapy was most frequently initiated with a β-lactam plus a macrolide,   38 Published by University of Chicago Press; ©2005 The University of Chicago Press. All rights reserved. b Switch = intravenous (IV) β-lactam + macrolide with pharmacist intervention to switch to oral quinolone. c Sequential = pharmacist-initiated automatic switch from IV to oral moxifloxacin. that since 3-day therapy did not result in inferior clinical results for these patients, short-course therapy is a more efficient strategy for treatment of CAP.
The current IDSA/ATS guidelines now recommend that patients with CAP should receive treatment for a minimum of 5 days, though patients should be afebrile for 48-72 hours and should have no more than one CAP-associated sign of clinical instability before discontinuation of therapy. 36 A longer duration of treatment may be needed for some patients, such as those whose initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, such as meningitis or endocarditis.

Summary
The costs of treating patients with CAP can increase significantly with antimicrobial resistance and treatment failure. Therefore, strategies should be employed to minimize these risks. Such strategies include early appropriate therapy, optimized dosing strategies based on pharmacodynamic principles, and efficient IV-to-PO switch when appropriate. Moreover, the use of shortcourse regimens that take advantage of available potent therapies provides a new opportunity to optimize clinical outcomes, improve medication adherence, and reduce the burden of prolonged antimicrobial exposures. ($215) periods (P < 0.001). Similarly, total antimicrobial costs were lower as well ($119 vs. $230 and $233, respectively; P < 0.001).

Strategy to Minimize Emergence of Resistance and Reduce Overall Costs: Short-Course Therapy
Over the past few years, there has been a growing preference of shorter courses (5 days or less) of antimicrobial regimens to the traditionally longer courses (7-14 days) for the treatment of CAP. 1, 39 The rationale is that the availability of more potent agents allows for more rapid eradication of pathogens, and the shorter courses reduce selection pressure for resistance development by decreasing time of antimicrobial exposure and reduced total antimicrobial usage. 40 Other advantages of short-course regimens include improved safety (that is, reduced potential of drug-related adverse events), increased patient convenience and, thus, adherence to therapy, and potentially reduced costs. It should be noted that short-course regimens must be based on sound pharmacodynamic data and must achieve adequate tissue penetration in order to be successful.
Several studies have investigated the clinical effectiveness of short-course regimens. [41][42][43] Though these studies show that the efficacy of short-course regimens is comparable to the efficacy of longer courses, they tend to only include patients with mildto-moderate disease and/or who were primarily treated on an outpatient basis. A study by Dunbar et al., however, compared the 750 mg dose of levofloxacin for 5 days with 500 mg for 10 days for patients with mild-to-severe CAP. 44 The short-course regimen was comparable to the longer-course regimen, even for patients with severe disease (PSI Class IV). Interestingly, patients receiving the 750 mg dose experienced more rapid resolution of fever and other CAP-related symptoms. 45 The question that remains is whether short-course therapy can reduce overall health care costs. In a study from the Netherlands, a cost-minimization analysis was performed based on direct medical and indirect nonmedical costs for the 28 days following hospital admission for patients with mild-to-moderate CAP, who received either 3 days or 8 days of antimicrobial therapy. 46 The shorter course was not associated with any significant difference in clinical results compared with standard therapy. Lower costs were observed with short-course therapy during hospital admission, but some of the savings were offset by follow-up visits to primary health care providers (Table 6). Total savings with shortcourse therapy were approximately 4%. The authors concluded Containing Costs and Containing Bugs: Are They Mutually Exclusive? T he timely selection and administration of appropriate antimicrobial therapy can significantly impact treatment outcomes, especially in patients with severe or life-threatening infections. 1,2 In an effort to optimize antimicrobial therapy while reducing treatment-related costs, minimizing adverse events, and decreasing the risk of development of antimicrobial resistance, many institutions are implementing antimicrobial stewardship programs (ASPs).

Justification for ASPs
Though it is difficult to establish causal relationships (because multiple factors contribute to the development and persistence of antimicrobial resistance), ASPs have the potential to limit the emergence and spread of resistant pathogens. A number of observations have suggested an association between antimicrobial use and the emergence of resistance. First, in vivo selection of resistance during antimicrobial therapy can cause de novo resistance, which can quickly spread to other patients in the setting of poor infection control measures (i.e., improper hand hygiene techniques or environmental contamination). Second, patients harboring a resistant organism (when transferred to a particular unit) may introduce the resistant strain. Third, resistance genes can also be transferred between organisms to create new resistant organisms. Fourth, ASPs attempt to reduce antimicrobial pressures that have been shown to promote resistance development. [3][4][5] For example, several studies have reported parallel changes in antimicrobial use and the prevalence of resistance. [6][7][8][9] Prior antimicrobial use is common in patients with health careassociated infections caused by resistant strains. 10 Areas within hospitals with higher rates of antimicrobial resistance also tend to have higher rates of antimicrobial use. 9 Increasing the duration of antimicrobials also increases the risk for colonization with resistant organisms.
Antimicrobial stewardship aims to promote the appropriate use of antimicrobials-the right selection, duration, dose, and route of administration. Promoting the appropriate use of antimicrobials is intended to improve clinical outcomes by reducing the emergence of resistance, limiting drug-related adverse events, and minimizing the risk of unintentional consequences associated with antimicrobial use (such as an increased risk of Clostridium difficile infection). 3,11,12 ASPs also have the potential to reduce antimicrobial costs by limiting the overuse and inappropriate use of these agents and by promoting active intravenous-to-oral (IV-to-PO) switch therapy. By reducing the unnecessary use of antimicrobials, a well-designed ASP has the additional advantages of reducing (a) the risk of drug-related adverse events and their associated costs, and (b) the emergence of resistance and, hence, minimizing infections caused by resistant pathogens. Infections caused by resistant organisms are associated with poorer clinical outcomes, prolonged hospital length of stay (LOS), and higher overall costs compared to infections caused by susceptible organisms. [13][14][15] Therefore, by promoting the appropriate use of antimicrobials, ASPs can have a broad impact on improving clinical outcomes while reducing overall health care costs.

Stewardship Tactics
The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines 3 identify 2 core proactive evidence-based strategies for promoting antimicrobial stewardship: (1) formulary restriction and pre-authorization, and (2) prospective audit with intervention and feedback.
Formulary Restriction and Pre-Authorization. The strategy of formulary restriction and pre-authorization involves limiting the use of specified antimicrobials to certain approved indications. An antimicrobial committee creates guidelines pertaining to the approved use of agents. If necessary, designated personnel are made available for the approval process. The strategy leads to direct control over antimicrobial use at an institution and educational opportunities for prescribers when a request is made. The major disadvantage of this strategy is that prescribers can have a perceived loss of autonomy when making clinical decisions. Personnel also need to be available for consultation at all times. As with many ASP tactics, there is an initial cost to implement and monitor the effectiveness of such programs.
Formulary restrictions have been proven to impact antimicrobial use. 16,17 One intervention at the University of Kentucky Chandler Medical Center in 1999 involved multiple aspects: (a) the removal of ceftazidime and cefotaxime from the formulary, (b) the restriction of ceftriaxone and carbapenem use to only approved indications, (c) the addition of cefepime to the formulary, (d) the replacement of ciprofloxacin with levofloxacin on the formulary, and (e) a 72-hour stop order on all vancomycin requests. 16 Follow-up analysis evaluated antimicrobial use and resistance rates in selected organisms. In 2000, antimicrobial expenditures decreased by over $200,000 (despite an increase in inpatient days) and further declined by $600,000 as of 2002 (when compared to 1998 expenditures). Not surprisingly, ceftazidime, cefotaxime, and ceftriaxone use decreased by nearly 80% by 2002. Another benefit of the ASP has been a decrease in resistance rates of several important pathogens, including multidrugresistant P. aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA; Figures 1a and 1b). The benefits from implementing this program have shown to be persistent.
Prospective Audit With Intervention and Feedback. A strategy of prospective audit with intervention and feedback involves a daily review of targeted agents for appropriateness. Follow-up intervention, if necessary, involves contacting the prescriber to recommend alternative agents. This tactic requires an antimicrobial committee to develop guidelines for appropriate use of targeted agents, and personnel (usually clinical pharmacists) are needed to perform the reviews and follow-up communication on a daily basis. The advantage of this strategy is that prescribers do not experience any perceived loss of autonomy, particularly if suggested changes by the reviewers are voluntary. This tactic also allows opportunity for educating prescribers through follow-up.
When utilized in a medium-sized community teaching hospital in Boston, this strategy resulted in significant reductions in inappropriate use of broad-spectrum intravenous agents, particularly third-generation cephalosporins. 18 An antimicrobial management team (consisting of an infectious diseases physician and an infectious diseases-trained pharmacist) reviewed antimicrobial orders for all patients receiving parenteral thirdgeneration cephalosporins, aztreonam, parenteral fluoroquinolones, or imipenem. The recommendations of the antimicrobial management team were communicated to the prescribers via nonpermanent chart notes. Following the implementation of the program, parenteral antimicrobial use decreased steadily from Year a Source: Martin et al. 16 terns. 3 However, it is important to note that antimicrobial selection is only one component of these recommendations. Diagnosis and testing, admission criteria, nursing care, conversion to oral medication, and discharge planning can also impact quality of care and resource utilization. 3 One study that incorporated a critical pathway at 20 hospitals for patients with CAP showed an 18% decrease in admissions for low-risk patients and significantly lower LOS and duration of IV therapy when compared to conventional therapy, resulting in significant cost savings. 20 Antimicrobial order forms can be an effective tactic to decrease antimicrobial consumption by implementing automatic stop orders and/or requiring physicians to justify antimicrobial use. 21 However, prescribers may view the process of filling out these forms as inconvenient and time consuming. The transition to computerized data entry systems at institutions may improve the use and convenience of such strategies.
Streamlining or de-escalation can decrease antimicrobial exposure and save costs when empiric therapy involves a combination of agents to ensure broad-spectrum coverage. Once culture results identify the pathogen, a planned removal of antimicrobials that are not necessary or that provide redundant coverage is initiated to provide more targeted therapy. For example, if vancomycin is initially included in the treatment regimen but culture results show an absence of MRSA, vancomycin can then be removed. This approach can lead to substantial cost savings without affecting clinical outcomes. 22,23 Dose optimization, an important part of antimicrobial stewardship, takes into account factors such as the pharmacokinetics and pharmacodynamics of the agent, patient and pathogen 1994 to 1998 while costs of parenteral antimicrobials decreased by nearly 30% (Figure 2), despite a 15% increase in the Medicare Case Mix Index and a 56% increase in ICU patient-days. The effect of this strategy on resistance and nosocomial infections was less clear. The rate of Clostridium difficile infection showed an initial decrease in 1993 and remained fairly steady after this (Figures 3a and 3b). 18 Similarly, the number of infections caused by ceftazidime-resistant Enterobacteriaceae decreased following implementation of the program, followed by a steady rate until 1996 and then a decrease again in 1997 and 1998. However, vancomycin-resistant enterococci (VRE) were first isolated in 1995 and their number grew dramatically in 1996. MRSA rates did not seem to be affected by the program and grew steadily. 18 Supplemental Strategies. Other supplemental strategies can also play a pivotal role in ASPs. 3 These include education, guidelines and clinical pathways, antimicrobial order forms, streamlining or de-escalation, dose optimization, and IV-to-PO switch.
Education is essential for any program that is designed to influence prescribing behaviors. Programs are needed to disperse information in an accurate and timely fashion. Since personnel can change over time, it is also important that the message be repeated routinely. Effective implementation of ASPs will incorporate education along with active strategies, such as prospective audit and intervention. 19 Guidelines and clinical pathways can improve antimicrobial utilization by multidisciplinary development of evidence-based guidelines that incorporate local microbiology and resistance pat-Antimicrobial Stewardship Programs: How to Start and Steer a Successful Program   1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year Resistant Isolates (%)

Stewardship Tactics at Various Stages of Patient Management
Stewardship tactics can be used at the various stages of managing a patient with an infectious disease ( Figure 4). 31 During patient evaluation, clinician education as well as management guidelines can aid in the proper diagnosis and the further actions needed (admission, laboratory testing, etc). Selecting the initial antimicrobial can also be impacted by education and the implementation of guidelines, as well as any formulary restriction and preauthorization policies. Computer-assisted strategies can be useful during the stage of antimicrobial selection, while a review and feedback strategy can help provide additional educational opportunities to the prescriber and offer a chance to adjust therapy and amend prescribing practices.

Impact of ASPs
Though more data are needed to demonstrate the benefits of the programs, ASPs have the potential to reduce resistance, health care costs, and drug-related adverse events while improving clinical outcomes. The impact of ASPs on bacterial resistance can be difficult to assess due to the multiple factors that can influence resistance development and spread. Optimized antimicrobial use is thought to help reduce the emergence of resistance, though few prospective randomized trials have attempted to analyze this. 32 Other studies that have attempted to assess various strategies to minimize resistance development usually have multiple confounding variables that can make it difficult to attribute any impact to one tactic. However, as discussed earlier, given an apparent association between antimicrobial use and the emergence of resistance, ASPs that reduce the inappropriate use of antimicrobials will decrease the selection pressure for the emergence of resistance. The IDSA/SHEA guidelines report that comprehensive programs can lead to a reduction in antimicrobial use by 22%-36%, resulting in significant cost savings. 3 The study by Martin et al., characteristics, and the site of infection when selecting the most appropriate antimicrobial regimen. Dose optimization strategies may include prolonged infusion of β-lactams, extended dosing intervals of aminoglycosides, or higher doses of fluoroquinolones to ensure that pharmacokinetic-pharmacodynamic targets are met. [24][25][26] IV-to-PO switch, discussed in the article by Dr. Nicolau in this supplement, is an effective tactic to decrease the LOS and health care costs.
The role of antimicrobial cycling in antimicrobial stewardship is not clear; insufficient data are available to recommend this strategy for routine use. Antimicrobial cycling involves the deliberate scheduled removal and substitution of specific antimicrobials or classes of antimicrobials within an institution to avoid or reverse the emergence of antimicrobial resistance. 27 As the scheduled antimicrobial is changed on a regular basis, adherence can be difficult with these programs mainly because prescribers may be unaware of the current scheduled antimicrobial. 28 The routine use of combination therapy is not recommended given a lack of data supporting its impact on preventing resistance development or improving outcomes. 29 However, empiric combination therapy can be important when treating severely ill patients to ensure early adequate coverage of potential pathogens. 30 Once culture results are available, de-escalation of therapy is recommended to provide targeted therapy and reduce antimicrobial exposure. 3,30 Antimicrobial Stewardship Programs: How to Start and Steer a Successful Program  1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year (57% vs. 49.9%, P = 0.02). Furthermore, once the ASP evaluated new antimicrobial orders for continuation of therapy, a significantly higher percentage of orders made after the ASP approval period was discontinued. The difference was most profound for orders originating from the surgical unit. This study suggests that physicians were more likely to wait until after the ASP approval period ended to order restricted antimicrobials without prior approval. These orders were more often found to be in conflict with guidelines or were unnecessary and hence discontinued. Finally, prescribers should receive positive feedback on a regular basis, and audits should be conducted routinely to monitor the effectiveness of the program.

Barriers to ASPs
Despite the many benefits of ASPs in improving antimicrobial use and clinical outcomes while reducing costs, several barriers exist that may hinder their implementation. Foremost is finding the appropriate personnel who are willing to devote the extra time and effort towards developing and enforcing ASPs. This barrier is further exacerbated by the fact the few clinicians receive additional compensation for the added responsibility. A survey by the Emerging Infectious Diseases Network found that only 18% of respondents were compensated for added responsibility. 36 Hospital administration may be hesitant to fund such programs without a guarantee of future pharmacy savings. Implementing tactics for an effective ASP will require funding to compensate those involved in the planning and monitoring of such programs. Further study is needed to understand the economic impact of ASPs as current reports are limited to single-center, longitudinal studies. 17,18,[38][39][40][41] However, these reports consistently show a decrease in antimicrobial use ranging from 22% to 36% and annual cost savings of $200,000 to $900,000 at both large academic medical centers 17,18,38,39 and smaller community hospitals. 40,41 These savings should more than offset any additional cost in implementing an ASP.
Another barrier is that ASP team members may not want to antagonize colleagues in other specialties as this can damage relationships and the potential for future consultations. This barrier may be circumvented by using a prospective audit with feedback tactic that makes any recommendation voluntary rather than mandatory and allows for educational opportunities. Other barriers for acceptance of ASPs may include a loss of physician autonomy pertaining to clinical decision making, a shortage of infectious diseases-trained pharmacists, restriction policies that can be onerous to adopt, and the continued need to assess the success of a program in order to sustain efforts.

Future Direction of Antimicrobial Stewardship
The IDSA/SHEA guidelines provide institutions with information needed when considering implementing an ASP. With more and more institutions implementing ASPs, it is anticipated that a growing number of studies will become available to better assess their impact-particularly, how the appropriate use of antimicrobials may impact the emergence of bacterial resistance. With the growing use of computerized order-entry and decision-support systems, ASPs may also become easier to implement and enforce while still providing opportunities to discuss with clinicians the appropriate use of antimicrobials. The greatest challenge may be in finding qualified personnel willing and able to direct such programs at each institution. presented earlier, demonstrated how a policy of formulary restriction and pre-authorization can result in substantial pharmacy cost savings. 16 These programs can provide substantial economic benefits irrespective of the size of the institution.
The impact of ASPs on clinical outcomes and adverse events can also be difficult to measure given the multifactorial nature of these issues. In one example of prospective audit and feedback, the rate of C. difficile infections decreased and remained stable after implementation of the program. 18 ASPs that reduce overall antimicrobial usage by minimizing the inappropriate use of these agents will have the potential to decrease the risk of drug-related adverse events and unintended consequences.

Implementing an ASP
The rationale, design, and implementation of ASPs have been described extensively in the medical literature. 3,31,[33][34][35] Creating an ASP involves multiple steps. 32 Baseline information should be obtained pertaining to antimicrobial use, expenditure, and institutional bacterial susceptibilities derived from the hospital antibiogram. This can help identify recurrent problems with antimicrobial use at the institution, such as overuse of a particular class or failure to switch from IV-to-PO when appropriate. An antimicrobial management strategy should be formulated, and an antimicrobial stewardship team with welldefined responsibilities formed. A multidisciplinary approach should be considered when selecting the ASP team members. The IDSA/SHEA guidelines recommend that the 2 core members of the team should include an infectious diseases physician and a clinical pharmacist with infectious diseases training. 3 Other critical members of the team can include a clinical microbiologist, a hospital epidemiologist, an infection control professional, and an information system specialist.
It is important to obtain support from the hospital administration as well as build relationships within the institution to help gain acceptance of the program once implemented. The hospital administration should give core team members the authority to enforce stewardship tactics. The ASP team members should also be fairly compensated for the additional time and effort needed to implement the ASP. One survey of infectious diseases consultants identified lack of compensation as a major barrier to implementing ASPs. 36 Prior to implementation of a program, the ASP team should negotiate the expected outcomes with hospital administration, which should be measurable and attainable.
Physician acceptance is extremely important during the design and implementation of an ASP. Adherence to ASPs should be monitored on a regular basis in order to identify ways in which physicians may try to circumvent ASP policies. One study described the experience at the University of Pennsylvania, where requests for restricted antimicrobials from 8:00 a.m. to 10:00 p.m. must be approved by an infectious diseases-trained pharmacist or infectious diseases fellow. 37 However, outside of these active ASP hours, restricted antimicrobials may be ordered without prior approval, though all orders still require approval by the ASP for continuation of treatment. The study evaluated whether prescribers were waiting until after the approval period ended (10:00 p.m.) for ordering restricted antimicrobials. Antimicrobial orders over a 3-month period were compared from one hour before (9:00-9:59 p.m.) and one hour after (10:00-10:59 p.m.) the ASP approval period. A greater proportion of antimicrobials ordered after the ASP approval period was for restricted antimicrobials